Asymmetric synthesis of 3,4-diaminocyclohexanol and endo -7-azabicyclo[2.2.1]heptan-2-amine

Article abstract of DOI:10.1021/ol102103y

Hydroboration of (1R,2R)-bis[(S)-1-phenylethylamino]cyclohex-4-ene and its derivatives with several borane reagents gave diastereomeric mixtures of the 3,4-diaminocyclohexanol derivatives. Cyclization of the prevalent diastereomer with the R configuration

Full text of DOI:10.1021/ol102103y

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4964-4967
Asymmetric Synthesis of
3,4-Diaminocyclohexanol and
endo-7-Azabicyclo[2.2.1]heptan-2-amine
Diego Savoia,* Stefano Grilli, and Andrea Gualandi
Dipartimento di Chimica “G. Ciamician”, UniVersita` di Bologna, Via Selmi 2,
40126 Bologna, Italy
diego.saVoia@unibo.it
Received September 3, 2010
ABSTRACT
Hydroboration of (1R,2R)-bis[(S)-1-phenylethylamino]cyclohex-4-ene and its derivatives with several borane reagents gave diastereomeric mixtures
of the 3,4-diaminocyclohexanol derivatives. Cyclization of the prevalent diastereomer with the R configuration of the newly formed stereocenter
under Mitsunobu conditions, followed by reductive removal of the N-substituents, gave the optically pure endo-7-azabicyclo[2.2.1]heptane-2-amine.
The 7-azabicyclo[2.2.1]heptane skeleton is present in a
variety of biologically and pharmacologically active com-
pounds.1 Chiral 7-azabicyclo[2.2.1]heptan-2-amines, endo-1
and exo-1 (Figure 1), are relatively unexplored compounds
despite their usefulness as structural fragments of more
complex, biologically and pharmacologically active mol-
ecules. Racemic endo-1 was prepared in five steps starting
from N-Boc-pyrrole exploiting a cycloaddition reaction with
a 3-bromopropargylic ester to construct the bicyclic skeleton
and Curtius rearrangement to form the 2-amino substituent.
Then, introduction of the endo-7-azabicyclo[2.2.1]heptan-
2-yl substituent at N6 of adenosine under SNAr conditions
afforded a reasonably potent A1 agonist 2a, while the
corresponding N7-Boc-derivative 2b was a highly potent
A1AR agonist.2 The racemic compound 3, prepared through
the cycloaddition of N-Boc-pyrrole with an acetylenic sulfone
followed by Michael addition of a benzylic amine, displayed
potent activity against PM I, II, and IV. Further, the two
enantiomers were resolved by preparative chiral HPLC, and
the IC50 values of the (-)-enantiomer were 2-fold better than
Figure 1
. Endo- and exo-7-azabicyclo[2.2.1]heptan-2-amines and
(1) Chen, Z.; Trudell, M. L. Chem. ReV. 1996, 96, 1179–1193.
(2) Ashton, T. D.; Aumann, K. M.; Baker, S. P.; Schiesser, C. H.;
Scammels, P. J. Bioorg. Med. Chem. Lett. 2007, 17, 6779–6784.
compounds containing these motifs.
10.1021/ol102103y  2010 American Chemical Society
Published on Web 10/08/2010

those of the racemate.3 The analogous preparation of N7-
and C-substituted derivatives of exo-1, which were particu-
larly active as R7 nicotinic acetylcholine receptors, was
reported in a patent.4 A longer sequence of steps, also
including a cycloaddition step of N-Boc pyrrole and a
resolution step, was necessary to prepare the dihydroxy
derivatives exo- and endo-4, which were active as glycosidase
inhibitors.5
These previously described routes led to racemic com-
pounds which were resolved to the enantiomers, considerably
reducing the yield of the desired optically pure compounds.
Hence, we envisioned an alternative asymmetric synthesis
of (+)- and (-)-endo-1 starting from enantiomerically pure
trans-1,2-diaminocyclohex-4-ene derivatives which are easily
prepared in two steps from the glyoxal diimines derived from
(R)- or (S)-1-phenylethanamine, e.g., 5 (Scheme 1).6,7 Our
Our first attempt was to perform a hydroboration reaction
on the diaminocyclohexene derivative 5 because the hy-
droboration of N,N′-bis[1(S)-phenylethyl]-4(R),5(R)-diami-
noocta-1,7-diene, the precursor of 5,6 was previously de-
scribed using 9-BBN.8 In our hands, using freshly prepared
9-BBN (2.5 equiv), a partial conversion of the alkene
function to give the alcohol 8 (ca. 20%, dr 3:1) was observed
by 1H NMR analysis of the crude product obtained after the
usual treatment with H2O2-NaOH (Scheme 2). In further
Scheme 2. Preparation of
N,N′-Disubstituted-3,4-diaminocyclohexanols 8a,b
Scheme 1. Planned Route to endo-1
experiments carried out increasing progressively the amounts
of 9-BBN up to 10 equiv, the conversion of 5 to the alcohol
8 (dr 75:25) progressively raised to 98%. The diastereoiso-
mers 8a and 8b were obtained pure by column chromatog-
raphy (SiO2) in 62% and 18% yield, respectively. Fractions
containing both diastereoisomers were also eluted (7%). The
equatorial and axial dispositions of the OH substituent in
the cyclohexane ring in 8a and 8b, respectively, were
assessed by NMR studies and later confirmed by the
outcomes of the subsequent ring closure step.
Other commercially available reagents, including BH3·Et3N,
BH3·PPh3, catecholborane, and BHBr2·SMe2, proved ineffective.
However, the use of BH3·SMe2 (3 equiv) allowed us to obtain
a moderate conversion to the diaminocyclohexanols 8a and 8b.
Increased amounts of the borane reagent, more forcing condi-
tions for the oxidative step, and increased reaction times did
not raise the yield of 8 over 50% (dr 65:35, determined by 1H
NMR analysis). The starting material was totally consumed,
but other compounds were present in the crude mixture and
were collected together in the first fractions eluted by column
chromatography. They are presumably organoboron species, but
their structure could not be determined.
Aiming to avoid formation of such boron-nitrogen species
and, if possible, to increase the diastereoselectivity, we
thought to protect the secondary amines of 5 by forming the
aminal with formaldehyde, as this protection can be readily
accomplished as well as removed (Scheme 3). Actually, the
aminal 9 was quantitatively formed by reaction of 5 with an
excess of paraformaldehyde in dichloromethane. Then, the
hydroboration occurred smoothly using 2.5 equiv of
BH3·SMe2 followed by oxidation. Column chromatography
(SiO2) afforded the inseparable mixture of 10a,b in 70% yield
(10a/10b ) 60:40). Also eluted were the cyclohexane
idea was to exploit the reactivity of the cyclohexene function
to introduce a substituent with leaving group ability and the
proper stereochemistry, as in structure 6. This compound
would undergo easy ring closure by nucleophilic displace-
ment by the trans-disposed amino group to give the bicyclic
compound 7. Then, routine hydrogenolysis would afford the
desired compound endo-1.
(3) (a) Hof, F.; Schu¨tz, A.; Fa¨h, C.; Meyer, S.; Bur, D.; Liu, J.; Goldberg,
D. E.; Diederich, F. Angew. Chem., Int. Ed. 2006, 45, 2138–2141. (b)
Zu¨rcher, M.; Gottschalk, T.; Meyer, S.; Bur, D.; Diederich, F. ChemMed-
Chem. 2008, 3, 237–240.
(4) Wishka, D. G.; Walker, D. P.; Corbett, J. W.; Reitz, S. C.;
Rauckhorst, M. R.; Groppi, V. E., Jr. Substituted 7-aza[2.2.1]bicycloheptanes
for the treatment of deseases, EP 1 425 286 B1, 2004.
(5) Moreno-Vargas, A. J.; Schu¨tz, C.; Scopelliti, R.; Vogel, P. J. Org.
Chem. 2003, 68, 5632–5640.
(6) Alvaro, G.; Grilli, S.; Martelli, G.; Savoia, D. Eur. J. Org. Chem.
1999, 1523–1526.
(7) Racemic trans- and cis-1,2-diaminocyclohex-4-ene were used to
prepare all the diastereomers of 4,5-diaminocyclohexan-1,2-diols: Witiak,
D. T.; Rotella, D. P.; Filippi, J. A.; Gallucci, J. J. Med. Chem. 1987, 30,
1327–1336. Witiak, D. T.; Wei, Y. J. Org. Chem. 1991, 56, 5408–5417
N,N′-(Boc)2-(S,S)-1,2-diaminocyclohex-4-ene was prepared by a long
sequence of steps including the catalytic asymmetric ring opening of the
N-(3,5-dinitro)benzoyl derivative of cyclohexa-1,4-diene monoaziridine:
Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2006, 128, 6312–6313.
(8) Alexakis, A.; Tomassini, A.; Chouillet, C.; Roland, S.; Mangeney,
P.; Bernardinelli, G. Angew. Chem., Int. Ed. 2000, 39, 4093–4095.
Org. Lett., Vol. 12, No. 21, 2010
4965

Scheme 3
.
Hydroboration of the Aminal Derivative 9
Scheme 4. Hydroboration of the Ditosylate 13
have been reported for the construction of the 7-azabicyclo-
[2.2.1]heptane skeleton by Mitsunobu-type protocols.1 Par-
ticularly, the cyclization of 4-benzylaminocyclohexanol was
achieved by reaction with PPh3/CCl4,11 and the PPh3/DEAD
system was employed in the total synthesis of epibatidine.12
In our hands, the reaction of 8a with PPh3/DIAD in toluene
occurred smoothly to give the desired bicyclic product 7
together with the cyclohexenes 5 and 14 in the relative ratio
80:12:8, as detected by GC-MS analysis (Scheme 5). The
product 7 was isolated in 65% yield, and its structure was
confirmed by NMR studies and NOE experiments.
Scheme 5
.
Synthesis of (-)-7-Azabicyclo[2.2.1]heptan-2-amine
Bishydrochloride
derivative 11 (20% yield) and a mixture of the four possible
regio- and diastereoisomers of N-methyl derivatives 12 (10%
overall). The latter compounds resulted from an unexpected
cleavage/rearrangement of the aminal moiety. A similar but
somewhat different rearrangement was reported for an
aminoborane complex coming from the diborane reduction
of benzooxazole and sulfur and selenium analogues.9 Hy-
drolysis of the compounds 10a,b dissolved in THF, with 2
N HCl at 80 °C for 5 h, finally gave the diaminoalcohols
8a,b in 75% yield after column chromatography.
We also prepared the diaminocyclohexene ditosylate salt
13, which was chosen for its solubility in organic solvents.
Complete conversion of the starting material was observed
yet when 6 equiv of BH3·SMe2 was used, whereas no
byproduct or borane complexes were observed in the crude
product after oxidation. The yield of the isolated mixture of
8a,b was 75%; however, the dr was nearly 1:1 (Scheme 4).
It should be underlined that the optically pure intermediates
8a,b are valuable molecules, as oxygen-substituted diami-
nocyclohexanes are potent opioid analgesics, and have been
heretofore prepared only as racemic compounds.10
Under the same conditions, the diastereoisomer 8b was
not completely consumed and was mainly converted to the
cyclohexenes 5 (24%) and 14 (48%) after chromatographic
separation, although minor amounts of the bicyclic compound
7 (15%) and unreacted 8b (15%) were recovered. The
different reactivity of 8b with respect to 8a is explained by
the axial disposition of the OH group, which is prone to
undergo dehydration by an anti-elimination mechanism.
The final step to obtain the N,N′-unsubstituted endo-7-
azabicyclo[2.2.1]heptan-2-amine 1 was the reductive removal
The diastereoisomer 8a had the correct configuration of
the secondary alcohol allowing ring closure by the nucleo-
philic attack of the amino group present at the opposite C4
of the cyclohexane ring. In the past, only a few examples
(9) Knapp, K. K.; Keller, P. C.; Rund, J. V. J. Chem. Soc., Chem.
Commun. 1978, 971.
(10) (a) Clark, C. R.; Halfpenny, P. R.; Hill, R. G.; Horwell, D. C.;
Hughes, J.; Jarvis, T. C.; Rees, D. C.; Schofield, D. J. Med. Chem. 1988,
31, 831–836. (b) Halfpenny, P. R.; Horwell, D. C.; Hughes, J.; Hunter,
J. C.; Rees, D. C. J. Med. Chem. 1990, 33, 286–291. (c) Schlichter, W. H.;
Frahm, A. W. Tetrahedron: Asymmetry 1992, 3, 329–332.
(11) Hassner, A.; Belostotskii, A. M. Tetrahedron Lett. 1995, 36, 1709–
1712.
(12) Sestanj, K.; Melenski, E.; Jirkovsky, I. Tetrahedron Lett. 1994, 35,
5417–5420.
4966
Org. Lett., Vol. 12, No. 21, 2010

of the benzylic substituents by hydrogenation in the presence
of palladium hydroxide in methanol in the presence of 2.5
equiv of HCl/MeOH. By this way, the dihydrochloride of
(-)-endo-(1R,2R,4S)-1 was obtained in 97% yield after
simple filtration of the heterogeneous catalyst (Scheme 6).
alcohol 8a which had the required configuration for the
efficient cyclization to the bicyclic compound 7. Although
separation of the diastereoisomers 8a and 8b was achieved
by column chromatography, ring closure by a Mitsunobu
protocol would be conveniently achieved on the diastereoi-
someric mixture 8a,b because 8b also partially underwent
cyclization to 7, which was easily separated from unreacted
8b and byproducts (cyclohexenes).
It is noteworthy that both enantiomers of endo-7-aza-
bicyclo[2.2.1]heptane-2-amine 1 are available by the de-
scribed route since the chiral auxiliary that was removed from
7 by routine hydrogenolysis is commercially available in
either S or R configurations.
Scheme 6. Synthesis of
(+)-endo-7-Azabicyclo[2.2.1]heptane-2-amine Bishydrochloride
Further transformations of the diaminocyclohexene 5, e.g.,
by epoxidation and cis-dihydroxylation of the CdC bond,
are currently investigated in our laboratory.
Acknowledgment. This work was carried out in the field
of the Prin Project: “Sintesi e stereocontrollo di molecole
organiche mediante metodologie innovative e di interesse
applicativo”. Support from the University of Bologna is
gratefully acknowledged.
In conclusion, the first asymmetric synthesis of endo-2-
amino-7-azabicyclo[2.2.1]heptane, endo-1, has been achieved
through the hydroboration of the chiral 1,2-diaminocyclohex-
4-ene 5 exploiting the asymmetric induction of (S)-1-
phenylethylamine as the chiral auxiliary. 9-BBN is the
reagent of choice to perform the hydroboration reaction
directly on 5, despite a large excess (10 equiv) of this reagent
being required to achieve an almost complete conversion to
the desired 3,4-diaminocyclohexanol 8. This was obtained
with a moderate diastereoselectivity in favor of equatorial
Supporting Information Available: Experimental pro-
cedures, full spectroscopic data, and copy of NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL102103Y
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